4-(4-{3-[4-chloro-3-(trifluoromethyl)phenyl]ureido}phenoxy)-N2-methylpyridine-2-carboxamide is commonly known as sorafenib (I). Sorafenib is prepared as its tosylate salt. Sorafenib blocks the enzyme RAF kinase, a critical component of the RAF/MEK/ERK signaling pathway that controls cell division and proliferation; in addition, sorafenib inhibits the VEGFR-2/PDGFR-beta signaling cascade, thereby blocking tumor angiogenesis.
Sorafenib, marketed as Nexavar™ by Bayer, is a drug approved for the treatment of advanced renal cell carcinoma (primary kidney cancer). It has also received “Fast Track” designation by the FDA for the treatment of advanced hepatocellular carcinoma (primary liver cancer). It is a small molecular inhibitor of RAF kinase, PDGF (platelet-derived growth factor), VEGF receptor 2 and 3 kinases and c Kit the receptor for stem cell factor.

Sorafenib and pharmaceutically acceptable salts thereof is disclosed in WO0042012. Sorafenib is also disclosed in WO0041698. Both these patents disclose processes for the preparation of sorafenib.
WO0042012 and WO0041698 describe the process as given in Scheme I which comprises reacting picolinic acid (II) with thionyl chloride in dimethyl formamide (DMF) to form acid chloride salt (III). This salt is then reacted with methylamine dissolved in tetrahydrofuran (THF) to give carboxamide (IV). This carboxamide when further reacted with 4-aminophenol in anhydrous DMF and potassium tert-butoxide 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline (V) is formed. Subsequent reaction of this aniline with 4-chloro-3-(trifluoromethyl)phenyl isocyanate (VI) in methylene chloride yields sorafenib (I). The reaction is represented by Scheme I as given below.

WO2006034796 also discloses a process for the preparation of sorafenib and its tosylate salt. The process comprises reacting 2-picolinic acid (II) with thionyl chloride in a solvent inert toward thionyl chloride without using dimethyl formamide to form acid chloride salt (III). This acid salt on further reaction with aqueous solution methylamine or gaseous methylamine gives compound (IV). Compound (IV) is then reacted with 4-aminophenol with addition of a carbonate salt in the presence of a base to yield compound (V).
Compound (V) can also be obtained by reacting compound (IV) with 4-aminophenol in the presence of water with addition of a phase transfer catalyst. Compound (V) when reacted with 4-chloro-3-(trifluoromethyl)phenyl isocyanate (VI) in a non-chlorinated organic solvent, inert towards isocyanate gives sorafenib (I). Sorafenib by admixing with p-toluenesulfonic acid in a polar solvent gives sorafenib tosylate (VII). The reaction is represented by Scheme II as given below.

A key step in the synthesis of sorafenib is the formation of the urea bond. The processes disclosed in the prior art involve reactions of an isocyanate with an amine. These isocyanate compounds though commercially available are very expensive. Further synthesis of isocyanate is very difficult which requires careful and skillful handling of reagents.
Isocyanate is prepared by reaction of an amine with phosgene or a phosgene equivalent, such as bis(trichloromethyl) carbonate (triphosgene) or trichloromethyl chloroformate (diphosgene). Isocyanate can also be prepared by using a hazardous reagent such as an azide. Also, the process for preparation of an isocyanate requires harsh reaction conditions such as strong acid, higher temperature, etc. Further, this isocyanate is reacted with an amine to give urea.
Reactions of isocyanates suffer from one or more disadvantages. For example, phosgene or phosgene equivalents are hazardous and dangerous to use and handle on a large scale. These reagents are also not environmentally friendly. Isocyanates themselves are thermally unstable compounds and undergo decomposition on storage and they are incompatible with a number of organic compounds. Thus, the use of isocyanate is not well suited for industrial scale application.
Hence, there is a need to develop simple and less hazardous process for large scale production. There is also a need to avoid, as far as possible, the use of hazardous chemicals and a need to use safer reagents which can be stored, handled without special precaution, and which are environmentally friendly.